Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates (preprint)

Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.

Network-based integrative multi-omics approach reveals biosignatures specific to COVID-19 disease phases. (preprint)

Background: COVID-19 disease is characterized by a spectrum of disease phases (mild, moderate, and severe). Each disease phase is marked by changes in omics profiles with corresponding changes in the expression of features (biosignatures). However, integrative analysis of multiple omics data from different experiments across studies to investigate biosignatures at various disease phases is limited. Exploring an integrative multi-omics profile analysis through a network approach could be used to determine biosignatures associated with specific disease phases and enable the examination of the relationships between the biosignatures. Aim: To identify and characterize biosignatures underlying various COVID-19 disease phases in an integrative multi-omics data analysis. Method: We leveraged the correlation network approach to integrate transcriptomics, metabolomics, proteomics, and lipidomics data. The World Health Organization (WHO) Ordinal Scale (WOS) was used as a disease severity reference to harmonize COVID-19 patient metadata across two studies with independent data. A unified COVID-19 knowledge graph was constructed by assembling a disease-specific interactome from the literature and databases. Disease-state omics-specific graphs were constructed by integrating multi-omics data with the unified COVID-19 knowledge graph. We expanded on the network layers of multiXrank, a random walk with restart on multilayer network algorithm, to explore disease state omics-specific graphs and perform enrichment analysis. Results: Network analysis revealed the biosignatures involved in inducing chemokines and inflammatory responses as hubs in the severe and moderate disease phases. We observed more shared biosignatures between severe and moderate disease phases as compared to mild-moderate and mild-severe disease phases. We further identified both biosignatures that discriminate between the disease states and interactions between biosignatures that are either common between or associated with COVID-19 disease phases. Interestingly, cross-layer interactions between different omics profiles increased with disease severity. Conclusion: This study identified both biosignatures of different omics types enriched in disease-related pathways and their associated interactions that are either common between or unique to mild, moderate, and severe COVID-19. These biosignatures include molecular features that underlie the observed clinical heterogeneity of COVID-19 and emphasize the need for disease-phase-specific treatment strategies. In addition, the approach implemented here can be used for other diseases.

Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

Between paradigms: Comparing experiences for adolescents treated at pediatric and adult trauma centres.

INTRODUCTION: Injured adolescents may be treated at pediatric trauma centres (PTCs) or adult trauma centres (ATCs). Patient and parent experiences are an integral component of high-quality health care and can influence patient clinical trajectory. Despite this knowledge, there is little research on differences between PTCs and ATCs with respect to patient and caregiver-reported experience. We sought to identify differences in patient and parent-reported experiences between the regional PTC and ATC using a recently developed Patient and Parent-Reported Experience Measure. METHODS: We prospectively enrolled patients (caregivers) aged 15-17 (inclusive), admitted to the local PTC and ATC for injury management (01/01/2020 - 31/05/2021) We provided a survey 8-weeks post-discharge to query acute care and follow-up experience. Patient and parent experiences were compared between the PTC and ATC using descriptive statistics, chi-square tests for categorical and independent t-tests for continuous variables. RESULTS: We identified 90 patients for inclusion (51 PTC, and 39 ATC). From this population, we had 77 surveys (32 patient and 35 caregiver) completed at the PTC, and 41 (20 patient and 21 caregiver) at the ATC. ATC patients tended to be more severely injured. We identified few differences in reported experience on the patient measure but identified lower ratings from caregivers of adolescents treated in ATCs for the domains of information and communication, follow-up care, and overall hospital scores. Patients and parents reported poorer family accommodation at the ATC. CONCLUSION: Patient experiences were similar between centres. However, caregivers report poorer experiences at the ATC in several domains. These differences are multifaceted, and may reflect differing patient volumes, effects of COVID-19, and healthcare paradigms. However, further work should target information and communication improvement in adult paradigms given its impact on other domains of care.

RESET-APP: ein App-basiertes Angebot zur Selbstregulation für Schüler*innen der Sekundarstufe I – Akzeptanz und Nutzungsverhalten

ZusammenfassungHintergrundDie COVID-19-Pandemie („coronavirus disease 2019") hat immense Auswirkungen auf die psychische Gesundheit. Kinder und Jugendliche gelten hierbei als besonders vulnerabel. Deshalb sind gerade für sie Angebote zur Gesundheitsförderung und Prävention wichtig. Gesundheitsförderung sollte motivierend gestaltet werden, um für diese Altersgruppe attraktiv zu sein. Ziel dieser Arbeit war zu untersuchen, ob Jugendliche mithilfe von innovativen digitalen Formaten erreicht werden können.MethodikEs wurde ein App-basiertes Training zur Förderung der Selbstregulation für die Sekundarstufe I konzipiert und Jugendlichen der Sekundarstufe I im Herbst 2020 angeboten. Hier wurde u. a. die Art der Motivation zur Teilnahme am Training abgefragt. Zudem konnten die Schüler*innen die Attraktivität des Trainings abschließend bewerten.ErgebnisVon den registrierten Schüler*innen (n = 91) absolvierten 39,56 % das komplette Training. 40,91 % der Schüler*innen, die das Training vollständig absolviert haben, gaben an, dass das Training „sehr" hilfreich war, 36,36 % bewerteten es als „ziemlich" hilfreich. 50 % der Befragten fand das App-basierte Training „modern und motivierend", die andere Hälfte hätte sich jedoch mehr persönliche Betreuung gewünscht.SchlussfolgerungDie Ergebnisse decken sich mit den Ergebnissen bereits veröffentlichter Studien: Heranwachsende sind zwar prinzipiell offen für digitale Formate, jene werden aber kaum verbindlich und kontinuierlich genutzt.

Changes in Inpatient Electroconvulsive Therapy Utilization Between 2019 and 2020: A National Inpatient Sample Analysis.

OBJECTIVES: Electroconvulsive therapy (ECT) is an essential procedure for a range of psychiatric conditions. Multiple single-center studies have documented reduction in ECT administration in 2020 because of the coronavirus disease 2019 pandemic, but there have been little nationally representative data from the United States. The aim of this study was to examine the demographics of patients receiving ECT in 2019 and 2020 and to characterize temporal and regional variations in ECT utilization. METHODS: The 2019 and 2020 National Inpatient Sample, an administrative database of inpatient hospitalizations in the United States, was queried for hospitalizations involving the delivery of ECT based on procedural codes. Overall number of ECT procedures was calculated based on the overall number of ECT procedural claims. RESULTS: In the 2019 NIS, 14,230 inpatient hospitalizations (95% confidence interval, 12,936-15,524) involved the use of ECT, with a cumulative 52,450 inpatient ECT procedures administered. In 2020, the number of inpatient hospitalizations with ECT decreased to 12,055 (95% confidence interval, 10,878-13,232), with a 10.0% reduction in overall procedures to 47,180. Whereas January and February ECT hospitalizations were comparable in both years, ECT hospitalizations decreased by more than 25% in March through May 2020 relative to 2019 volume. There was regional variability in the change in ECT utilization between 2019 and 2020. CONCLUSIONS: Electroconvulsive therapy use among general hospital inpatients declined between 2019 and 2020, with regional variability in the magnitude of change. Further study is warranted into the root causes and optimal responses to these changes.

Delivering the Right Care at the Right Time and Place

The March 2023 issue of NEJM Catalyst Innovations in Care Delivery shows health care organizations overcoming obstacles to develop cutting-edge programs to meet patients' needs. This issue of NEJM Catalyst Innovations in Care Delivery contains articles, case studies, and research reports on retail health, telehealth in a conflict zone, equitable access to Covid-19 antivirals, dementia care, screening for adverse childhood experiences, and the ongoing health care workforce crisis.

Using Haplotype-Based Artificial Intelligence to Evaluate SARS-CoV-2 Novel Variants and Mutations.

Importance: Earlier detection of emerging novel SARS-COV-2 variants is important for public health surveillance of potential viral threats and for earlier prevention research. Artificial intelligence may facilitate early detection of SARS-CoV2 emerging novel variants based on variant-specific mutation haplotypes and, in turn, be associated with enhanced implementation of risk-stratified public health prevention strategies. Objective: To develop a haplotype-based artificial intelligence (HAI) model for identifying novel variants, including mixture variants (MVs) of known variants and new variants with novel mutations. Design, Setting, and Participants: This cross-sectional study used serially observed viral genomic sequences globally (prior to March 14, 2022) to train and validate the HAI model and used it to identify variants arising from a prospective set of viruses from March 15 to May 18, 2022. Main Outcomes and Measures: Viral sequences, collection dates, and locations were subjected to statistical learning analysis to estimate variant-specific core mutations and haplotype frequencies, which were then used to construct an HAI model to identify novel variants. Results: Through training on more than 5 million viral sequences, an HAI model was built, and its identification performance was validated on an independent validation set of more than 5 million viruses. Its identification performance was assessed on a prospective set of 344 901 viruses. In addition to achieving an accuracy of 92.8% (95% CI within 0.1%), the HAI model identified 4 Omicron MVs (Omicron-Alpha, Omicron-Delta, Omicron-Epsilon, and Omicron-Zeta), 2 Delta MVs (Delta-Kappa and Delta-Zeta), and 1 Alpha-Epsilon MV, among which Omicron-Epsilon MVs were most frequent (609/657 MVs [92.7%]). Furthermore, the HAI model found that 1699 Omicron viruses had unidentifiable variants given that these variants acquired novel mutations. Lastly, 524 variant-unassigned and variant-unidentifiable viruses carried 16 novel mutations, 8 of which were increasing in prevalence percentages as of May 2022. Conclusions and Relevance: In this cross-sectional study, an HAI model found SARS-COV-2 viruses with MV or novel mutations in the global population, which may require closer examination and monitoring. These results suggest that HAI may complement phylogenic variant assignment, providing additional insights into emerging novel variants in the population.

Impact of the COVID-19 Pandemic on Patient Satisfaction After Total Joint Arthroplasty.

The coronavirus disease 2019 (COVID-19) pandemic impacted the inpatient experience before and after total joint arthroplasty (TJA). This study aimed to examine how these changes affected patient satisfaction following TJA as recorded by Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) postdischarge surveys and comments at 2 large academic institutions. A retrospective review identified patients who completed HCAHPS surveys following primary and revision TJA at 2 academic institutions: 1 in a predominately rural southern state (Institution A) and 1 in a northeastern metropolitan city (Institution B). Patients were grouped by discharge date: pre-COVID-19 (April 1, 2019, to October 31, 2019) or COVID-19 affected (April 1, 2020, to October 31, 2020). Differences in demographics, survey responses, and comment sentiments and themes were collected and evaluated. The number of HCAHPS surveys completed increased between periods at Institution A but decreased at Institution B (Institution A, 61 vs 103; Institution B, 524 vs 296). Rates of top-box survey responses remained the same across the 2 periods. The number of comments decreased at Institution B (1977 vs 1012) but increased at Institution A (55 vs 88). During the COVID-19-affected period, there was a significant increase in the negative comment rate from Institution B (11.6% vs 14.8%, P=.013) and a significant decrease in the positive comment rate from Institution A (70.9% vs 44.3%, P<.001). There was an increase in negative patient sentiments following TJA during the COVID-19 pandemic as seen in qualitative comments but not quantitative responses. This suggests that certain aspects of the TJA patient experience were impacted by COVID-19. [Orthopedics. 2023;46(2):e105-e110.].

TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques.

The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163+MRC1-, and TREM2+ populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.

Telehealth Rapid Access Chest Pain Clinic: Initial Experience During COVID-19 Pandemic.

Objectives: Rapid Access Chest Pain Clinics (RACPCs) provide safe and efficient follow-up for outpatients presenting with new-onset chest pain. RACPC delivery by telehealth has not been reported. We sought to evaluate a telehealth RACPC established during the coronavirus disease 2019 (COVID-19) pandemic. There was a need to reduce the frequency of additional testing arranged by the RACPC during this time, and the safety of this approach was also explored. Methods: This was a prospective evaluation of a cohort of RACPC patients reviewed by telehealth during the COVID-19 pandemic compared with a historical control group of face-to-face consultations. The main outcomes included emergency department re-presentation at 30 days and 12 months, major adverse cardiovascular events at 12 months, and patient satisfaction scores. Results: One hundred forty patients seen in the telehealth clinic were compared with 1,479 in-person RACPC controls. Baseline demographics were similar; however, telehealth patients were less likely to have a normal prereferral electrocardiogram than RACPC controls (81.4% vs. 88.1%, p = 0.03). Additional testing was ordered less often for telehealth patients (35.0% vs. 80.7%, p < 0.001). Rates of adverse cardiovascular events were low in both groups. One hundred twenty (85.7%) patients reported being satisfied or highly satisfied with the telehealth clinic service. Conclusions: In the setting of COVID-19, a telehealth RACPC model with reduced use of additional testing facilitated social distancing and achieved clinical outcomes equivalent to a face-to-face RACPC control. Telehealth may have an ongoing role beyond the pandemic, supporting specialist chest pain assessment for rural and remote communities. Pending further study, it may be safe to reduce the frequency of additional testing following RACPC review.

Community belongingness during COVID-19 predicts anxiety and depression treatment change in college students.

Objective Community belongingness has been shown to be related to mental health outcomes in college students; however, little work has evaluated whether community belongingness impacts treatment change, especially during the COVID-19 pandemic, when social isolation and mental health concerns are exacerbated. Accordingly, the current study evaluated community belongingness as a predictor of treatment change for anxiety and depression in a university counseling center. Method: Participants included 516 young adults with clinical levels of anxiety or depression who attended at least two individual therapy sessions at a university counseling center during fall 2020. Participants completed broad measures of psychosocial functioning at each session. Results: Paired-samples t-tests indicated that students demonstrated significant decreases in anxiety and depression after just one session. Linear stepwise regressions revealed that community belongingness was a significant predictor of symptom improvement for both anxiety and depression. Conclusion: These results suggest improving community belongingness on college campuses may be a way to buffer mental health and improve treatment outcomes for students seeking psychological services. Specific clinical and educational recommendations for ways to improve community belongingness are discussed.

5-year follow-up of adolescents with social anxiety disorder: Current functioning during COVID-19.

The present study followed-up adolescents with social anxiety disorder (SAD) during the COVID-19 pandemic, approximately 5-years following their participation in an Attention Bias Modification Training (ABMT) program (Ollendick et al., 2019). The current study aimed to evaluate current functioning and quality of life (QoL) during the emerging adulthood period. Participants included 27 young adults who completed a randomized controlled trial of ABMT and were available for follow-up. Participants filled out self-report measures of QoL and functioning and underwent a clinical interview to assess current severity of social anxiety. Clinician-rated symptoms of SAD significantly decreased from post-treatment to 5-year follow-up. Additionally, results demonstrated that social anxiety severity was significantly related to poorer self-reported physical and psychological health as well as poorer functioning with regard to social distancing fears during COVID-19. Lastly, when evaluating change in symptoms over time, increases in social anxiety severity over a 5-year period significantly predicted worsened social distancing fears during COVID-19.

IgG4 serum levels are not elevated in cases of Post-COVID syndrome (preprint)

The different effector functions of human IgG are closely associated with its four subtypes. Class switch towards IgG4 occurs after long-term antigen exposure, downregulates immune responses and is associated with several autoimmune diseases. Interestingly, significantly elevated IgG4 levels have recently been detected after more than two mRNA vaccinations. We here study the distribution of IgG subtypes in the context of Post-COVID syndrome. To this end, we analyzed serum samples from two cohorts of 64 patients after COVID and 64 convalescent COVID-19 patients. We found differences in the absolute levels of Spike protein-specific IgG subtypes for both cohorts. IgG1 was the most abundant subtype, followed by IgG3 and IgG2 and IgG4 in declining order. A significant difference was only detected for IgG2. When further analyzing the IgG4 levels reactive against the Spike protein receptor-binding domain (RBD) and the nucleocapsid-protein of SARS-CoV-2, a small but significant difference was detected for the RBD but not nucleocapsid proteins. Since the total IgG4 levels are very low, we do not expect a biologically relevant role in the development and progression of post-COVID syndrome. However, low IgG2 levels, as seen in the Post-COVID cohort, could contribute to the persistent presence of SARS-CoV-2 antigens, causing chronic inflammation in the setting of post-COVID.

Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53-4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

Co-Occurring Catatonia and COVID-19 Diagnoses Among Hospitalized Individuals in 2020: A National Inpatient Sample Analysis.

BACKGROUND: COVID-19 is associated with a range of neuropsychiatric manifestations. While case reports and case series have reported catatonia in the setting of COVID-19 infection, its rate has been poorly characterized. OBJECTIVE: This study reports the co-occurrence of catatonia and COVID-19 diagnoses among acute care hospital discharges in the United States in 2020. METHODS: The National Inpatient Sample, an all-payors database of acute care hospital discharges, was queried for patients of any age discharged with a diagnosis of catatonia and COVID-19 in 2020. RESULTS: Among 32,355,827 hospitalizations in the 2020 National Inpatient Sample, an estimated 15,965 (95% confidence interval: 14,992-16,938) involved a diagnosis of catatonia without COVID-19 infection, 1,678,385 (95% confidence interval: 1,644,738-1,712,022) involved a diagnosis of COVID-19 without a co-occurring catatonia diagnosis, and 610 (95% confidence interval: 578-642) involved both catatonia and COVID-19 infection. In an adjusted model, a diagnosis of COVID-19, but not a diagnosis of catatonia or the combination of catatonia and COVID-19, was associated with increased mortality. Patients with catatonia and COVID-19 were frequently diagnosed with encephalopathy and delirium codes. CONCLUSIONS: Catatonia and COVID-19 were rarely co-diagnosed in 2020, and catatonia diagnosis was not associated with increased mortality in patients with COVID-19. Further research is needed to better characterize the phenomenology of catatonia in the setting of COVID-19 infection and its optimal treatment.

First results from post-COVID inpatient rehabilitation.

Background: COVID-19 is associated with various symptoms and psychological involvement in the long term. In view of the multifactorial triggering and maintenance of the post-COVID syndrome, a multimodal therapy with somatomedical and psychotherapeutic content is expedient. This paper compares the psychological stress of post-COVID patients and their course in rehabilitation to psychosomatic and psychocardiological patients. Method: Observational study with control-groups and clinical, standardized examination: psychological testing (BDI-II, HELATH-49), 6-MWT as somatic parameter, two measurement points (admission, discharge). Sample characteristics, including work related parameters, the general symptom-load and the course of symptoms during rehabilitation are evaluated. Results: At admission in all measures post-COVID patients were significantly affected, but less pronounced than psychosomatic or psychocardiological patients (BDI-II post-COVID = 19.29 ± 9.03, BDI-II psychosomatic = 28.93 ± 12.66, BDI-II psychocardiology = 24.47 ± 10.02). During rehabilitation, in all complaint domains and sub-groups, symptom severity was significantly reduced (effect sizes ranging from d = .34 to d = 1.22). Medium positive effects were seen on self-efficacy (d = .69) and large effects on activity and participation (d = 1.06) in post-COVID patients. In the 6-MWT, the walking distance improved by an average of 76.43 ± 63.58 meters (d = 1.22). Not a single patient deteriorated in walking distance, which would have been a possible sign of post exercise malaise (PEM). Conclusion: Post-COVID patients have a slighter psychological burden as psychocardiological or psychosomatic patients. Although rehabilitation is not curative, post-COVID patients benefit significantly from the interventions and there were no signs of PEM.

A New Way to Distribute Research Seed Funding: Peer Review without Formal Review

As some of the most stable and important structures in society, colleges and universities are rarely described as nimble. Yet, when the COVID-19 pandemic hit in March 2020, institutions across the globe not only shifted within days to online instruction, but many academic researchers also immediately launched efforts to understand the virus, identify treatments, produce medical supplies, and study its impacts. While some investigators managed to make progress, other talented researchers lacked timely access to funding for key personnel, lab supplies, and incentives for study participants--the needed fuel for discoveries. Even as researchers have long called for low-barrier processes to accelerate time-sensitive research contributions, the pandemic has painfully underscored the need for rapid responses to pressing societal needs. Experimental programs offer models of the funding mechanisms needed to heighten efficiency, whether in the face of COVID or other ongoing crises. In this article, the authors discuss the shortcomings of the current, widely used peer review process and suggest that Mcubed, a novel token-based review and funding program developed at the University of Michigan (U-M), may offer significant advantages. This article describes the operation of Mcubed over an 8-year period on U-M's three campuses and details the positive results that were obtained, hoping to motivate others to engage in comparable endeavours.